When Haley Well was born in 2006, doctors were initially afraid that the baby wouldn’t survive. “She was so blue that they thought she wasn’t getting any oxygen,” recalled her mother, Jordana Well.
Early blood work revealed that the newborn had a dangerously low platelet count and her blood wasn’t clotting properly. Genetic tests then showed that Haley suffered from a rare inherited bone marrow disorder called congenital amegakaryocytic thrombocytopenia (CAMT).
CAMT can lead to life-threatening bleeding episodes, and the only thing that ultimately cures CAMT is a bone marrow transplant from a tissue-matched donor. Haley underwent a transplant at eight months old — an experience her mother described as “a nightmare,” owing to the repeated rounds of chemotherapy, with all the attendant side effects.
Although Haley’s blood now clots properly — thanks to a German bone marrow donor whose identity was revealed last year — the five-year-old still suffers from complications of the treatment: Chronic diarrhea has meant that she has yet to be toilet trained, and she has difficulty walking.
As a result, whether Haley will start school with her peers in September is still up in the air. “The public school automatically has her in kindergarten, but the Jewish private school here in D.C. thinks she might need another year,” said Well, a documentary filmmaker in Washington.
Both Well and her husband, Ranan, are Ashkenazi Jews, with predominantly Russian and Polish lineages. Unlike many couples with similar backgrounds, they did not undergo genetic screening before conceiving. But even if they had, testing would not have revealed their genetic predisposition to the disease, as no current Ashkenazi Jewish genetic disease assays include CAMT on their panels.
That isn’t surprising, considering that fewer than 100 cases of the disease have ever been described, according to a review published in this August’s issue of Pediatric Blood & Cancer. But new findings suggest that CAMT may have long gone undiagnosed, particularly in the Jewish community.
In April, Berish Rubin, a professor and molecular geneticist at Fordham University in New York, together with colleagues from the Haredi organizations Dor Yeshorim and Bonei Olam, reported in the journal Blood Cells, Molecules, and Diseases that about 1 in 75 Ashkenazi Jews harbor the genetic defect responsible for CAMT.
If two people with the mutation responsible for CAMT have a baby, there’s a one in four chance that their child with be affected by the disease. Considering the large number of genetic carriers found in the study by Rubin’s team, one would expect about one in 22,500 Ashkenazi Jewish babies to be born with the disease.
But they’re not. “The carrier frequency is such that one would expect to see it occur much more in the population than we’re actually seeing,” explained Rubin.
So, “the question is: Where are the children?” said study co-author Chaim Jalas, director of genetic resources and services at Bonei Olam, a Brooklyn-based organization that assists couples struggling with infertility. “The answer is probably that most are not born.”
Rubin, Jalas and their colleagues were first alerted to the genetic association in the Jewish community after an Orthodox Jewish couple with a sick child approached Bonei Olam for help. The couple had already had five miscarriages, and their fourth child was born with a large blood stain on his right leg — the hallmark of a clotting problem.
Suspecting CAMT, which is caused by mutations in a gene called MPL, the research team tested the DNA of the parents and the child and quickly confirmed the diagnosis. They then went back and looked at blood samples from more than 2,000 people of Ashkenazi Jewish descent and found the same mutation in 27 unrelated individuals.
Several companies — including GeneDx, PreventionGenetics and BloodCenter of Wisconsin — now offer genetic tests for CAMT. Rubin advised that “women who are having late-term miscarriages should be tested for the presence of this mutation.”
Genetic testing for CAMT could also conceivably be offered to all Ashkenazi Jewish couples who are planning a family. In June, the Chicago Center for Jewish Genetic Disorders upped the number of diseases it screens to 19, from 9. But “if carrier testing became widely available [for CAMT], it would be reasonable to consider adding this test to the others we currently screen for,” said Michelle Gilats, a genetic counselor with the organization.
Meanwhile, the Victor Center for the Prevention of Jewish Genetic Diseases “will look further into the implications of screening for CAMT in terms of availability of testing and whether this mutation accounts for 90% or more of Jewish mutations for this disease,” according to Dr. Jodi Hoffman, director of the Victor Outreach and Screening Program for Ashkenazi Jewish Genetic Diseases at Tufts Medical Center in Boston. The Philadelphia-based Victor Center is often the first research institute in the country to advise screening for diseases newly discovered to have a Jewish link.
Through community-wide genetic testing, couples who learn they are both genetic carriers could choose to undergo in vitro fertilization and implant only those embryos that are unaffected by the disease. Or they might still opt for natural conception, but armed with the advance knowledge that there’s a 25% chance of having a child with CAMT.
That information, according to Dr. David Jacobsohn, chief of the blood and marrow transplant program at Children’s National Medical Center in Washington, D.C., can help couples “prepare much earlier for curative therapy, such as a transplant.”
Contact Ellen Friedrichs at firstname.lastname@example.org